Summary/Abstract Migraine is an immense healthcare burden. Existing therapeutics are only fractionally effective since they may not adequately target underlying key causes - CNS hyperexcitability (HE) and oxidative stress (OS). Brain HE enhances OS and OS in turn promotes brain HE, including that seen in the trigeminal system (TS), a site involved in migraine pain. Unraveling this vicious cycle may lead to novel therapeutics for migraine. Our unique breakthrough came from research showing that increased physical and intellectual activity (EE) reduces OS and lowers susceptibility to spreading depression (SD), a model of migraine that begins with HE and includes nociceptive-HE in the TS. Human studies show that EE also reduces susceptibility to migraine while EE in animals prompts a rise in insulin-like growth factor-1 (IGF-1), which is neuroprotective. We are developing IGF-1 as a novel, naturally occurring migraine treatment since it reduces the HE / OS needed to trigger SD, and by extension we reason the HE / OS that occurs in the TS with migraine models. The General Goal of this proposal is to define the optimal IGF-1 dose in rats necessary to mitigate the TS activation that accompanies migraine (and is evident in our models) to inform subsequent translation to human clinical trials. Two models of migraine will be used to validate our therapeutic approach. Both will examine the impact of nasal administration IGF-1 on nociceptive activation of the TS. The project has two specific aims: AIM 1: Determine the dose range of IGF-1 needed to mitigate migraine modeled in rats using SD (model-1). IGF-1, will be given (every 3rd day for 2 weeks) via intranasal delivery and the impact on neocortical SD threshold (SDT) and related TS activation (i.e., c-fos, OS and CGRP levels) will be determined. Milestone: Determine the optimal dose of IGF-1 that mitigates migraine modeled in female and male rats. This data will provide the basis for selection of doses to be tested in subsequent toxicology studies to enable human clinical trials to determine if nasal IGF-1 can control migraine in human patients. AIM 2: Determine the dose range of IGF-1 needed to mitigate migraine modeled in rat via intravenous glyceryltrinitrate (GTN) infusion (model-2). IGF-1 will be administered (every 3rd day for 2 weeks) via intranasal delivery and impact on TS activation (see above) will be measured later, following 20 minutes of intravenous GTN infusion. Milestone: Validation in a second translational model and determine the dose of intranasally administered IGF-1 necessary to mitigate migraine in male and female rats. This data will provide secondary support for subsequent plans for the enablement of IND-enabling studies needed for clinical trials. This project is significant because it has high commercial value due to unmet needs of migraineurs and it is likely to establish the technical merit and feasibility of development of IGF-1 as a migraine therapeutic. Development of IGF-1 as a migraine remedy is innovative, as it is a naturally occurring EE-based signal, and is likely to work upstream of calcitonin gene related peptide (CGRP), a known trigger of migraine.